gms | German Medical Science

Objective: Atorvastatin (ATVS) is an inhibitor of the cholesterol pathway and pioglitazone (PGZ) is an agonist of Peroxisomal Proliferator Activator Receptor y. We have suspected the antitumor effect of the combination of these drugs in glioma cell cultures and in an animal model of glioma. The possible enhancement of the current treatment modality with temozolomide (TMZ) by adding ATVS and PGZ has not been assessed yet.

Method: We compared the anti-glioma effect of ATV, PGZ, TMZ, and their combinations at several concentrations on human malignant glioma cell lines U87 and LN405. The response was evaluated using a cell proliferation assay and the results were reported as percent of cell death in respect to untreated cells after 72 hours. The combination index was calculated.

Results: After 72 hours, on cell line LN405, we found a cell death rate of 33.5% with ATVS at 0.5 μM, of 42.3% with PGZ at 1 μM, and of 4.3% with TMZ at 150 μM. TMZ in combination with PGZ or ATVS led to a significant increase of the effect of TMZ (41.2% and 44.7% respectively). The highest effect was achieved by combining the 3 drugs (62.4%). This result was highly significant in comparison to each substance alone or to only two combined drugs. A cell death rate of 21.8% was achieved at the lowest (60 μg TMZ, 0.06 μg ATVS and 0.125 μg PGZ) and a rate of 65.0% at the highest concentrations (240 μg TMZ, 1.5 μg ATVS and 5 μg PGZ) tested in a combination of these three drugs. Similar results were obtained with the cell line U87. At low doses, we found a synergistic effect of the addition of ATVS or PGZ to TMZ.

Conclusions: The combination of ATVS and PGZ with TMZ leads to an enhancement of the anti-tumor effect or allows a reduction of the required doses. In vivo trials followed by phase I studies are warranted.